The clonal selection theory of adaptive immunity suggests that proliferation of a single lymphocyte should provide sufficient function for acute defense (effector cells), yet the regenerative capacity to maintain the selected lineage (memory cells). The progeny of a CD4+ helper T cell selected for an immune response against parasitic pathogens must also have the plasticity to choose among several effector lineages (Th1, Th2, Th17) in order to mobilize the most appropriate defense mechanisms for elimination of a single-celled intracellular protozoan or a multi-celled extracellular helminth. This proposal tests the hypothesis that signals directing the activation of a CD4+ helper T cell during the immune response against the parasite Leishmania major may trigger a program of cell fate diversity among the initial daughter cells of the selected microbe-specific T cell. Preliminary evidence suggests such diversification may be accomplished using an evolutionarily conserved mechanism, called asymmetric cell division, wherein critical cell fate determinants are inherited unequally by two daughter cells. This competing continuation proposal seeks to determine the extent of disparity in the inheritance of signaling molecules and fate regulators in the initial cellular progeny of a CD4+ helper T cell responding to L. major, to evaluate the fate of the initial daughter and grand-daughter CD4+ T cells, and to assess genetically whether critical daughter cell fates depend on regulators of asymmetric cell division. These studies should provide novel insight into some of the most important remaining questions regarding the programming of CD4+ helper T cell function and the immunological control of parasitic infections that are relevant to humankind.Public Health Relevance Statement Helper T lymphocytes are specialized white blood cells that orchestrate the actions of our immune system to protect us against infections. This project will reveal the inner workings of how helper T cells match their function appropriately to the type of infection we encounter, and how they prevent themselves from becoming depleted when the infection persists for our lifetime.